Cu(II)-Mediated Aminooxygenation of Alkenylimines and Alkenylamidines with TEMPO

Abstract

A method for the synthesis of oxymethyl dihydropyrroles (pyrrolines) and dihydroimidazoles has been developed via Cu(II)-mediated intramolecular aminooxygenation of alkenylim­ines and alkenylamidines, respectively, with 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO).

Key words

copper - TEMPO - dihydropyrroles (pyrrolines) - dihydroimidazoles

• References and Notes


For recent reviews, see:
• 1a Thomas GL, Johannes CW. Curr. Opin. Chem. Biol. 2011; 15: 516
• 1b Tohme R, Darwiche N, Gali-Muhtasib H. Molecules 2011; 16: 9665
• 1c Dandapani S, Marcaurelle LA. Curr. Opin. Chem. Biol. 2010; 14: 362
• 1d Welsch ME, Snyder SA, Stockwell BR. Curr. Opin. Chem. Biol. 2010; 14: 347
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For selected reviews, see:
• 2a Joule JA, Mills K. Heterocyclic Chemistry . 5th ed. Wiley-Blackwell; Chichester: 2010
• 2b Progress in Heterocyclic Chemistry . Vol. 20. Gribble GW, Joule JA. Elsevier; Oxford: 2008. and others in this series
• 2c Comprehensive Heterocyclic Chemistry III . Katritzky AR, Ramsden CA, Scriven EF. V, Taylor RJ. K. Pergamon; Oxford: 2008
• 2d Comprehensive Heterocyclic Chemistry II . Katritzky AR, Rees CA, Scriven EF. V, Taylor RJ. K. Pergamon; Oxford: 1996
• 2e Eicher T, Hauptmann S. The Chemistry of Heterocycles . Wiley-VCH; Weinheim: 2003
• 3 Zhang L, Ang GY, Chiba S. Org. Lett. 2010; 12: 3682
• 4 Sanjaya S, Chiba S. Tetrahedron 2011; 67: 590
• 5 Zhang L, Ang GY, Chiba S. Org. Lett. 2011; 13: 1622
• 6a Paderes MC, Belding L, Fanovic B, Dudding T, Keister JB, Chemler SR. Chem. Eur. J. 2012; 18: 1711
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• 6f Fuller PH, Kim J.-W, Chemler SR. J. Am. Chem. Soc. 2008; 130: 17638
• 7 For the copper-mediated diamination of alkenes in similar manner to the oxyamination, see: Sequeira FC, Turnpenny BW, Chemler SR. Angew. Chem. Int. Ed. 2010; 49: 6365
• 8 Pickard PL, Tolbert TL. J. Org. Chem. 1961; 26: 4886
• 9 The copper-catalyzed/-mediated aminooxygenation with sulfonamide and TEMPO generally needed high temperature (110–130 °C), see ref. 6
• 10 Zhang and Zhu reported copper-catalyzed aerobic reactions of N-allyl amidines that afforded formylimidazoles via aminooxygenation of the alkene, see: Wang H, Wang Y, Liang D, Liu L, Zhang J, Zhu Q. Angew. Chem. Int. Ed. 2011; 50: 5678
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• 12 The reactions might be initiated by aminocupration of putative copper iminyl species onto alkene followed by conversion of the resulting organocopper species into the C–O bond with TEMPO. For a review on synthetic applications of TEMPO, see: Vogler T, Studer A. Synthesis 2008; 1979

Recent literature precedents have shown that Cu(II) species and TEMPO make a Cu(III)–TEMPO complex that works as an ionic electrophile, see:
• 13a Wang Y.-F, Toh KK, Lee J.-Y, Chiba S. Angew. Chem. Int. Ed. 2011; 50: 5927
• 13b Van Humbeck JF, Simonovich SP, Knowles RR, MacMillan DW. C. J. Am. Chem. Soc. 2010; 132: 10012
• 13c Michel C, Belanzoni P, Gamez P, Reedjik J, Baerends EJ. Inorg. Chem. 2009; 48: 11909
• 13d It could also be proposed that the resulting Cu(III)–TEMPO complex induces electrophilic cyclization of the imino sp² nitrogen with the intramolecular alkene

There have been reported some biologically active natural alkaloids such as broussonetine and nectrisine bearing oxymethyl dihydropyrrole or pyrrolidine structures, see:
• 14a Merino P, Delso I, Tejero T, Cardona F, Marradi M, Faggi E, Parmeggiani C, Goti A. Eur. J. Org Chem. 2008; 2929
• 14b Hulme AN, Montgomery CH. Tetrahedron Lett. 2003; 44: 7649
• 15 We have tried oxidative and reductive cleavage of the O–N bond of 3aa (using MCPBA and Zn/MeOH–aq NH₄Cl conditions, respectively), while only decomposed complex mixtures were obtained
• 16 General Procedure for the Synthesis of 2,2,6,6-Tetramethyl-1-[(2,4,4-trimethyl-5-p-tolyl-3,4-dihydro-2H-pyrrol-2-yl)methoxy]piperidine (3aa) To a 10 mL Schlenk tube with a Teflon valve was added carbonitrile 1a (48.2 mg, 0.39 mmol) in Et₂O (0.4 mL) and p-tolylmagnesium bromide (2a, 0.53 mL, 0.47 mmol, 0.88 M in Et₂O) was added slowly. The reaction was then heated at 60 °C under sealed conditions for 4 h. The mixture was quenched with distilled MeOH (60 μL) at 0 °C, and DMF (4 mL), Cu(OAc)₂ (72.2 mg, 0.40 mmol), and TEMPO (91.7 mg, 0.59 mmol) were added immediately. The mixture was further stirred at r.t. for 2 h under an inert atmosphere. The reaction was quenched with ammonium buffer solution (pH 9) and extracted three times with Et₂O. The organic phase was then washed with H₂O and brine and dried over MgSO₄. The solvent was evaporated to give a crude mixture, which was purified by flash column chromatography (hexane–EtOAc = 95:5) to provide 3aa (98.7 mg, 0.27 mmol) in 68% yield. Analytical Data Colorless oil. IR (NaCl): 2968, 2932, 2870, 1609, 1468, 1360, 1312, 1244, 1132, 1070, 1053, 752, 731 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.07 (3 H, s), 1.13 (3 H, s), 1.20 (3 H, s), 1.24 (3 H, s), 1.32 (3 H, s), 1.36 (3 H, s), 1.44 (3 H, s), 1.27–1.51 (6 H, m), 1.68 (1 H, d, J = 12.8 Hz), 2.34 (1 H, d, J = 12.8 Hz), 2.36 (3 H, s), 3.79 (1 H, d, J = 8.4 Hz), 3.89 (1 H, d, J = 8.4 Hz), 7.16 (2 H, d, J = 8.2 Hz), 7.60 (2 H, d, J = 8.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 15.3, 18.6, 18.9, 19.6, 25.0, 26.3, 28.0, 31.4, 31.5, 38.0, 47.4, 50.0, 58.3, 70.5, 81.0, 126.3, 127.0, 130.6, 137.2, 175.8. ESI-HRMS: m/z calcd for C₂₄H₃₉N₂O [M + H]⁺: 371.3062; found: 371.3053
• 17 General Procedure for the Synthesis of 1-[(1,2-Diphenyl-4,5-dihydro-1H-imidazol-4-yl)methoxy]-2,2,6,6-tetramethylpiperidine (5a) To a 25 mL Schlenk tube was added amidine 4a (136.7 mg, 0.58 mmol), Cu(OAc)₂ (113.0 mg, 0.62 mmol), and TEMPO (135.5 mg, 0.87 mmol) in DMF (6.0 mL). The reaction was then heated at 80 °C for 24 h. The reaction was quenched with ammonium buffer solution (pH 9) at r.t. It was then extracted three times with EtOAc. The organic phase was then washed with H₂O and brine and dried over MgSO₄. The solvent was removed in vacuo, affording crude residue, which was purified by flash column chromatography (hexane–EtOAc = 80:20, gradually 20% EtOAc increment every time after 50 mL eluent, until 100% EtOAc was reached) to provide 5a (126.8 mg, 0.33 mmol) in 56% yield (94% purity). Analytical Data Yellow oil. IR (NaCl): 2932, 1614, 1595, 1574, 1495, 1470, 1385, 1360, 1300, 1283, 1134, 1051, 1028 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.97 (3 H, s), 1.08 (3 H, s), 1.17 (3 H, s), 1.24 (3 H, s), 1.42–1.49 (6 H, m), 3.95–3.98 (2 H, m), 4.05–4.08 (1 H, m), 4.22 (1 H, dd, J = 9.4, 9.9 Hz), 4.33–4.43 (1 H, m), 6.79 (2 H, d, J = 8.1 Hz), 6.96 (1 H, dd, J = 7.1, 7.4 Hz), 7.15 (2 H, dd, J = 7.6, 7.8 Hz), 7.25–7.29 (2 H, m), 7.35 (1 H, dd, J = 7.1, 7.4 Hz), 7.51 (2 H, d, J = 7.4 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 17.0, 19.9, 20.1, 33.1, 33.3, 39.6, 56.7, 60.0, 63.5, 78.6, 122.6, 123.1, 128.1, 128.2, 128.6, 128.7, 129.8, 131.3, 143.1. ESI-HRMS: m/z calcd for C₂₅H₃₄N₃O [M + H]⁺: 392.2702; found: 392.2701